Atheromatous lesions consist of numerous cellular and acellular elements. Macrophages are a major constituent of these lesions as they develop into characteristic cholesteryl ester-laden foam cells (Ross, R. (1986) New England J. Med. 314:488-500; Munro, J. M. and Cotran, R. S. (1988) Laboratory Invest. 58:249-261). For macrophages, foam cell development during atherogenesis is ultimately dependent upon uptake of various forms of low density lipoprotein (LDL) (reviewed in Brown, M. S. and Goldstein, J. L. Ann. Rev. Biochem. 52:223-261). Of late, emphasis has been placed on the importance of the interaction of chemically modified or oxidized LDL with macrophage scavenger receptors (reviewed in Steinberg, D., et al. (1988) New England J. Med. 320:915-924), which may occur during atherogenesis in vivo (Steinberg, D., et al. (1988) New England J. Med. 320:915-924; Haberland, M. E., et al. (1988) Science 241:215-218; Palinski, W., et al. (1989) Proc. Natl. Acad. Sci. USA 86:1372-1376; Rosenfeld, M. E., etal. (1990) Arteriosclerosis 10:336-349; Boyd, H. C., et al. (1990) Am. J. Path. 135:815-825).
Foam cell development may also be influenced by the interaction of lipoproteins with pathways other than those associated with scavenger receptors. In particular, recent studies have shown that immune complexes consisting of LDL bound to anti-LDL antibodies (LDL-IC) can cause foam cell development in vitro through interaction with IgG Fc receptors (Fc.gamma.R) when administered to both mouse (Klimov, A. N., et al. (1985) Atherosclerosis 58:1-15) and human macrophages (Lopes-Virella, M. F., et al. (1991) Arteriosclerosis and Thrombosis 11:1356-1367; Griffith, R. L., et al. (1988) J. Exp. Med. 168:1041-1059). LDL-IC (reviewed in Orekhov, A. N. (1991) Curr. Opin. Lipidology 2:329-333) consisting of antibodies bound to either native or oxidized LDL exist in numerous situations in vivo (Szondy, E., et al. (1983) Atherosclerosis 49:69-77; Parums, D. V., et al. (1990) Arch. Pathol. Lab. Med. 114:383-387; Beaumont, J. L., et al. (1988) Atherosclerosis 74:191-201; Kigore, L. L., et al. (1985) J. Clin. Invest. 76:225-232), and in several cases have been correlated with abnormalities of lipid metabolism and atherosclerosis (Szondy, E., et al., supra; Parums, D. V., et al., supra; Beaumont, J. L., et al., supra; Kigore, L. L., et al., supra; Cohen, L., et al. (1966) Am. J. Med. 40:299-316).
In contrast to the role of LDL in foam cell development, human high density lipoprotein (HDL) may play a role in preventing foam cell development. HDL is known to play a role in cholesterol efflux from extrahepatic tissues, such as vascular tissue, to the liver where it can be metabolized. See, e.g., Badimon, J. J. et al. (1992) Circulation (Supp. III) 86(6):III-86-III-94; Castell, W. P. et al (1977) Circulation 55(5):767-772. Moreover, it has been shown that plasma HDL both inhibits the development of experimental atherosclerosis and induces regression of the lipid infiltration into vessel (e.g., aortic) walls. Badimon, J. J. et al., supra.
Human Fc.gamma. receptors (Fc.gamma.R) (reviewed in Fanger, M. W., et al. (1989) Immunology Today 10:92-99), of which there are three structurally and functionally distinct types (i.e., Fc.gamma.RI, Fc.gamma.RII and Fc.gamma.RIII), are well-characterized cell surface glycoproteins that mediate phagocytosis or antibody-dependent cell cytotoxicity (ADCC) of immunoglobulin G (IgG) opsonized targets.
Bispecific antibody technology has been used to evaluate the function of specific Fc.gamma.R. Investigators have shown that Fc.gamma.R are the only cell surface molecules on myeloid cells capable of triggering phagocytic or cytotoxic function (Shen, L., et al. (1986) J. Immunol. 137:3378-3382; Shen, L. et al. (1987) J. Immunol. 139:534-538; Connor, R. I., et al. (1990) J. Immunol. 145:1483-1489; Anderson, C. L., et al. (1990) J. Exp. Med. 171:1333-1345). However, clear differences in the functional ability of the different Fc.gamma.R could be demonstrated that was dependent not only on the Fc.gamma.R class or isoform but on the state of activation and differentiation of the cell (Fanger, M. W., et al. (1989) Immunology Today 10:92-99; Van de Winkel, J. G. and Anderson, C. L. (1991) J. Leukocyte Biol. 49:511-524).